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Anthropogenic activities increase the level of dissolved heavy metals in some tropical near‐shore environments threatening reef ecosystems. The skeleton of stony corals like Porites species potentially provides a high‐resolution geochemical archive for past heavy metal concentrations, with potentially century long records revealing baseline values before large‐scale human disturbance. However, few data exist for heavy metal partitioning into coral skeleton aragonite. To address this, culturing experiments exposing Porites lobata and Porites lichen to a mixture of dissolved Cr, Mn, Ni, Cu, Zn, Ag, Cd, Sn, Hg, and Pb over a wide concentration range have been performed. Water samples were taken frequently to monitor changes in the heavy metal concentration. Laser ablation ICP‐MS measurements of the coral aragonite revealed metal concentrations that were positively correlated with Cr, Mn, Ni, Zn, Ag, Cd, and Pb concentrations in seawater. The DTE values for most metals appear dependent on the seawater metal content, approximating a power law, and therefore stabilize at higher seawater metal/Ca ratios. The partitioning of Pb into the coral skeleton is a notable exception, with DPb being stable around 2 to 1 across a large range of “natural” to highly polluted seawater Pb concentrations. This and the general agreement with partition coefficients estimated by previous work suggests that the reconstruction of the heavy metal concentration in seawater for ecosystem monitoring is possible. However, the high variability within and between coral colonies requires further study and suggests that multiple records from multiple coral colonies should be combined to obtain robust reconstructions. Key Points Porites corals grow normally with increased exposure to multiple metals over >1 year Skeletal partitioning variable within and between colonies and with seawater metal content Good agreement with previous work, especially for Pb across a large range of metal content

Living Ammonia species and an inventory of dead assemblages from Adriatic subtidal, nearshore environments were investigated at four stations off Bellaria, Italy. Ammonia falsobeccarii, Ammonia parkinsoniana, Ammonia tepida, and Ammonia veneta were recognized in the living (rose-bengal-stained) fauna, and Ammonia bellaria n. sp. is described herein for the first time. Ammonia beccarii was only found in the dead assemblage. The biometry of 368 living individuals was analysed by using light microscopic and scanning electron microscopic images of three aspects. A total of 15 numerical and 8 qualitative parameters were measured and assessed, 5 of which were recognized to be prone to a certain subjectivity of the observer. The accuracy of numerical data as revealed by the mean residuals of parallel measurements by different observers ranged from 0.5 % to 5.5 %. The results indicated a high degree of intraspecific variability. The test sizes of the individual species were log-normally distributed and varied among the stations. Parameters not related to the growth of the individuals, i.e. flatness of the tests, dimensions of the second-youngest chamber, proloculus, umbilical and pore diameter, sinistral–dextral coiling, and umbilical boss size, were recognized as being species-distinctive in combination. They may well supplement qualitative criteria that were commonly used for species discrimination such as a lobate outline, a subacute or rounded peripheral margin, or the degree of ornamentation on the spiral and umbilical sides. The averages of the measured parameters were often lower than the range of previously published values, mainly because the latter were retrieved from a few adult specimens and not from the whole assemblage as in the present approach. We conclude that the unprecedented high proportions of Ammonia beccarii in the northern Adriatic may well be artificial. A robust species identification without genetic analyses is possible by considering designated biometric parameters. This approach is also applicable to earlier literature data, and their re-assessment is critical for a correct denomination of recent genotypes.

In eukaryotes, the Dph1•Dph2 dimer is a non-canonical radical SAM enzyme. Using iron-sulfur (FeS) clusters, it cleaves the cosubstrate S-adenosyl-methionine (SAM) to form a 3-amino-3-carboxy-propyl (ACP) radical for the synthesis of diphthamide. The latter decorates a histidine residue on elongation factor 2 (EF2) conserved from archaea to yeast and humans and is important for accurate mRNA translation and protein synthesis. Guided by evidence from archaeal orthologues, we searched for a putative SAM-binding pocket in Dph1•Dph2 from Saccharomyces cerevisiae. We predict an SAM-binding pocket near the FeS cluster domain that is conserved across eukaryotes in Dph1 but not Dph2. Site-directed DPH1 mutagenesis and functional characterization through assay diagnostics for the loss of diphthamide reveal that the SAM pocket is essential for synthesis of the décor on EF2 in vivo. Further evidence from structural modeling suggests particularly critical residues close to the methionine moiety of SAM. Presumably, they facilitate a geometry specific for SAM cleavage and ACP radical formation that distinguishes Dph1•Dph2 from classical radical SAM enzymes, which generate canonical 5′-deoxyadenosyl (dAdo) radicals.

Marine carbon and nitrogen processing through microorganisms’ metabolism is an important aspect of the global element cycles. For that purpose, we used foraminifera to analyze the element turnover with different algae food sources. In the Baltic Sea, benthic foraminifera are quite common and therefore it is important to understand their metabolism. Especially, Cribroelphidium selseyense , also occurring in the Baltic Sea, has often been used for laboratory feeding experiments to test their effect on carbon or nitrogen turnover. Therefore, foraminifera were collected from the Kiel Fjord and fed with six different algal species in two qualities (freeze-dried algae vs. fresh algae, all 13 C- and 15 N-labeled). Also, labeled dissolved inorganic C and N compounds and glucose were offered to the foraminifera to test direct assimilation of dissolved compounds (carbon and nitrogen) from the water column. Our experiments showed that after 15 days of incubation, there were highly significant differences in isotope labeling in foraminifera fed with fresh algae and dry algae, depending on algal species. Further, different algal species led to different 13 C and 15 N enrichment in the studied foraminifera, highlighting a feeding preference for one diatom species and an Eustigmatophyte. A significant carbon assimilation from HCO 3 – was observed after 7 days of incubation. The N assimilation from NH 4 + was significantly higher than for NO 3 – as an inorganic N source. The uptake of glucose showed a lag phase, which was often observed during past experiments, where foraminifera were in a steady state and showed no food uptake at regular intervals. These results highlight the importance of food quality on the feeding behavior and metabolic pathways for further studies of foraminiferal nutrition and nutrient cycling.

Heavy metal pollution originating from anthropogenic sources, e.g. mining, industry and extensive land use, is increasing in many parts of the world and influences coastal marine environments even after the source has ceased to pollute. The elevated input of heavy metals into the marine system potentially affects the biota because of their toxicity, persistence and bioaccumulation. An emerging tool for environmental applications is the heavy metal incorporation into foraminiferal calcite tests, which facilitates monitoring of anthropogenic footprints on recent and past environmental systems. The aim of this study was to investigate whether the incorporation of heavy metals into foraminifera is a direct function of their concentration in seawater. Culturing experiments with a mixture of dissolved chromium (Cr), manganese (Mn), nickel (Ni), copper (Cu), zinc (Zn), silver (Ag), cadmium (Cd), tin (Sn), mercury (Hg) and lead (Pb) in artificial seawater were carried out over a wide concentration range to assess the uptake of heavy metals by the nearshore foraminiferal species Ammonia aomoriensis, Ammonia batava and Elphidium excavatum. Seawater analyses revealed increasing concentrations for most metals between culturing phases and high metal concentrations in the beginning of the culturing phases due to sudden metal addition. Furthermore, a loss of metals during the culturing process was discovered by an offset between the added and the actual concentrations of the metals in seawater. Laser ablation ICP-MS (inductively coupled plasma mass spectrometry) analysis of the newly formed calcite revealed species-specific differences in the incorporation of heavy metals. The foraminiferal calcite of all three species exhibited Pb and Ag concentrations strongly correlated with concentrations in the seawater culturing medium (partition coefficients and standard deviation for Ag – Ammonia aomoriensis, 0.50 ± 0.02; Ammonia batava, 0.17 ± 0.01; Elphidium excavatum, 0.47 ± 0.04; for Pb – Ammonia aomoriensis, 0.39 ± 0.01; Ammonia batava, 0.52 ± 0.01; Elphidium excavatum, 0.91 ± 0.01). Ammonia aomoriensis further showed a correlation with Mn and Cu, A. batava with Mn and Hg, and E. excavatum with Cr and Ni and partially also with Hg. However, Zn, Sn and Cd showed no clear trend for the species studied, which in the case of Sn was maybe caused by the lack of variation in the seawater Sn concentration. The calibrations and the calculated partition coefficients render A. aomoriensis, A. batava and E. excavatum as natural archives that enable the determination of variations in some heavy metal concentrations in seawater in polluted and pristine environments.

In eukaryotes, the Dph1•Dph2 dimer is a non-canonical radical SAM enzyme. Using iron-sulfur (FeS) clusters, it cleaves the cosubstrate S-adenosyl-methionine (SAM) to form a 3-amino-3-carboxy-propyl (ACP) radical for the synthesis of diphthamide. The latter decorates a histidine residue on elongation factor 2 (EF2) conserved from archaea to yeast and humans and is important for accurate mRNA translation and protein synthesis. Guided by evidence from archaeal orthologues, we searched for a putative SAM-binding pocket in Dph1•Dph2 from Saccharomyces cerevisiae. We predict an SAM-binding pocket near the FeS cluster domain that is conserved across eukaryotes in Dph1 but not Dph2. Site-directed DPH1 mutagenesis and functional characterization through assay diagnostics for the loss of diphthamide reveal that the SAM pocket is essential for synthesis of the décor on EF2 in vivo. Further evidence from structural modeling suggests particularly critical residues close to the methionine moiety of SAM. Presumably, they facilitate a geometry specific for SAM cleavage and ACP radical formation that distinguishes Dph1•Dph2 from classical radical SAM enzymes, which generate canonical 5′-deoxyadenosyl (dAdo) radicals.

BAK1 is a coreceptor and positive regulator of multiple ligand binding leucine-rich repeat receptor kinases (LRR-RKs) and is involved in brassinosteroid (BR)-dependent growth and development, innate immunity, and cell death control. The BAK1-interacting LRR-RKs BIR2 and BIR3 were previously identified by proteomics analyses of in vivo BAK1 complexes. Here, we show that BAK1-related pathways such as innate immunity and cell death control are affected by BIR3 in Arabidopsis thaliana. BIR3 also has a strong negative impact on BR signaling. BIR3 directly interacts with the BR receptor BRI1 and other ligand binding receptors and negatively regulates BR signaling by competitive inhibition of BRI1. BIR3 is released from BAK1 and BRI1 after ligand exposure and directly affects the formation of BAK1 complexes with BRI1 or FLAGELLIN SENSING2. Double mutants of bak1 and bir3 show spontaneous cell death and constitutive activation of defense responses. BAK1 and its closest homolog BKK1 interact with and are stabilized by BIR3, suggesting that bak1 bir3 double mutants mimic the spontaneous cell death phenotype observed in bak1 bkk1 mutants via destabilization of BIR3 target proteins. Our results provide evidence for a negative regulatory mechanism for BAK1 receptor complexes in which BIR3 interacts with BAK1 and inhibits ligand binding receptors to prevent BAK1 receptor complex formation.

Background The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin’s lymphoma population, primarily consisting of patients with DLBCL. Methods Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells. Results Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance. Conclusions AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing. Trial registration Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.

Kelps (Laminariales, Phaeophyceae) are foundation species along Arctic rocky shores, providing the basis for complex ecosystems and supporting a high secondary production. Due to ongoing climate change glacial and terrestrial run-off are currently accelerating, drastically changing physical and chemical water column parameters, e.g., water transparency for photosynthetically active radiation or dissolved concentrations of (harmful) elements. We investigated the performance and functioning of Arctic kelp holobionts in response to run-off gradients, with a focus on the effect of altered element concentrations in the water column. We found that the kelp Saccharina latissima accumulates harmful elements (e.g., cadmium, mercury) originating from coastal run-off. As kelps are at the basis of the food web, this might lead to biomagnification, with potential consequences for high-latitude kelp maricultures. In contrast, the high biosorption potential of kelps might be advantageous in monitoring environmental pollution or potentially extracting dissolved rare earth elements. Further, we found that the relative abundances of several kelp-associated microbial taxa significantly responded to increasing run-off influence, changing the kelps functioning in the ecosystem, e.g., the holobionts nutritional value and elemental cycling. The responses of kelp holobionts to environmental changes imply cascading ecological and economic consequences for Arctic kelp ecosystems in future climate change scenarios.

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT 4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT 4 R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT 4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform HTR4b_2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.